JP2013523184A5 - - Google Patents

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JP2013523184A5
JP2013523184A5 JP2013505101A JP2013505101A JP2013523184A5 JP 2013523184 A5 JP2013523184 A5 JP 2013523184A5 JP 2013505101 A JP2013505101 A JP 2013505101A JP 2013505101 A JP2013505101 A JP 2013505101A JP 2013523184 A5 JP2013523184 A5 JP 2013523184A5
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seq
heavy chain
binding protein
antigen binding
light chain
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Priority claimed from PCT/US2011/032333 external-priority patent/WO2011130417A2/en
Publication of JP2013523184A publication Critical patent/JP2013523184A/en
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（ａ）以下のうちの１つ以上を含む軽鎖ＣＤＲ３：
（i）配列番号１７〜２７のＬ１〜Ｌ１１のＣＤＲ３配列と、２つ以下のアミノ酸の付加、置換、欠失およびその組み合わせにより異なる軽鎖ＣＤＲ３配列；
（ii）ＭＱＡＸ１ＥＦＰＷＴ（配列番号１７４）；
（iii）ＧＴＷＤＳＳＬＳＸ２ＶＸ３（配列番号１７５）；
（iv）ＱＱＹＤＮＬＦＴ（配列番号１２２）；
（v）ＱＱＹＧＳＡＰＬＴ（配列番号１２３）；
（vi）ＶＬＹＭＧＳＧＩＷＶ（配列番号１２４）；
（vii）ＥＴＷＤＳＳＬＳＡＧＶ（配列番号１２７）；
ここで、
Ｘ１はＬまたはＩであり；
Ｘ２はＶまたはＡであり；および
Ｘ３はＶまたはＡである；
（ｂ）以下のうちの１つ以上を含む重鎖ＣＤＲ３：
（i）配列番号２８〜３８のＨ１〜Ｈ１１のＣＤＲ３配列と、１つ以下のアミノ酸付加、置換、欠失、およびまたはその組み合わせにより異なる重鎖ＣＤＲ３配列；
（ii）ＧＷＦＤＸ６（配列番号１７８）；
（iii）ＧＴＳＦＤＹ（配列番号９９）；
（iv）ＹＧＧＳＦＤＹ（配列番号１００）；
（v）ＭＶＹＶＬＤＹ（配列番号１０１）；
（vi）ＶＡＧＰＦＤＦ（配列番号１０２）；
ここで、
Ｘ６はＹ、ＩまたはＦである；並びに
（ｃ）（ａ）の軽鎖ＣＤＲ３配列および（ｂ）の重鎖ＣＤＲ３配列
のうちの１つ以上を含み、
β−Ｋｌｏｔｈｏと特異的に結合する、単離された抗原結合タンパク質。 (A) Light chain CDR3 comprising one or more of the following:
(I) a light chain CDR3 sequence that differs depending on the addition, substitution, deletion and combination of two or less amino acids to the CDR3 sequence of L1 to L11 of SEQ ID NOs: 17 to 27;
(Ii) MQAX 1 EFPWT (SEQ ID NO: 174);
(Iii) GTWDSSLSX 2 VX 3 (SEQ ID NO: 175);
(Iv) QQYDNLFT (SEQ ID NO: 122);
(V) QQYGSAPLT (SEQ ID NO: 123);
(Vi) VLYMGSGIWV (SEQ ID NO: 124);
(Vii) ETWDSSSLAGV (SEQ ID NO: 127);
here,
X 1 is L or I;
X 2 is V or A; and X 3 is V or A;
(B) Heavy chain CDR3 comprising one or more of the following:
(I) a heavy chain CDR3 sequence that differs by one or more amino acid additions, substitutions, deletions, or combinations thereof from a CDR3 sequence of H1-H11 of SEQ ID NOs: 28-38;
(Ii) GWFDX 6 (SEQ ID NO: 178);
(Iii) GTSFDY (SEQ ID NO: 99);
(Iv) YGGSFDY (SEQ ID NO: 100);
(V) MVYVLDY (SEQ ID NO: 101);
(Vi) VAGPFDF (SEQ ID NO: 102);
here,
X 6 is Y, I or F; and (c) comprises one or more of the light chain CDR3 sequence of (a) and the heavy chain CDR3 sequence of (b),
An isolated antigen binding protein that specifically binds to β-Klotho. 抗原結合タンパク質が、
（ａ）以下のうちの１つ以上を含む軽鎖ＣＤＲ１：
（i）配列番号１７〜２７のＬ１〜Ｌ１１のＣＤＲ１配列と２つ以下のアミノ酸付加、置換、欠失、およびその組み合わせにより異なる軽鎖ＣＤＲ１配列；
（ii）ＲＳＳＱＳＬＶＸ２２ＹＸ２３ＤＧＮＴＹＬＳ（配列番号１７７）；
（iii）ＳＧＳＳＳＮＩＧＮＮＹＶＳ（配列番号１０７）；
（vi）ＱＡＳＱＤＩＮＮＹＬＮ（配列番号１０８）；
（v）ＲＡＳＱＳＶＳＧＮＹＬＡ（配列番号１０９）；
（vi）ＧＶＳＳＧＳＶＳＴＲＹＹＰＳ（配列番号１１０）；
ここで、
Ｘ２２はＨであるかまたは存在せず；および
Ｘ２３はＳであるかまたは存在しない；
（ｂ）以下のうちの１つ以上を含む軽鎖ＣＤＲ２：
（i）配列番号１７〜２７のＬ１〜Ｌ１１のＣＤＲ２配列と、２つ以下のアミノ酸付加、置換、欠失、およびその組み合わせにより異なる軽鎖ＣＤＲ２配列；
（ii）ＫＩＳＮＲＦＳ（配列番号１１２）；
（iii）ＤＮＮＸ４ＲＰＸ５（配列番号１７６）；
（iv）ＤＴＳＮＬＥＴ（配列番号１１４）；
（v）ＧＡＳＳＲＡＴ（配列番号１１５）；
（vi）ＳＴＮＴＲＳＳ（配列番号１１６）；
ここで、
Ｘ４はＫ、ＮまたはＲであり；および
Ｘ５はＳであるかまたは存在しない；並びに
（ｃ）以下のうちの１つ以上を含む重鎖ＣＤＲ１：
（i）配列番号２８〜３８のＨ１〜Ｈ１１のＣＤＲ１配列と、３つ以下のアミノ酸付加、置換、欠失、およびその組み合わせにより異なる重鎖ＣＤＲ１配列；
（ii）Ｘ１９ＹＸ２０ＭＸ２１、
ここで、
Ｘ１９はＡ、Ｇ、Ｒ、Ｓ、Ｔ、またはＩであり；
Ｘ２０はＹ、ＧまたはＡであり；および
Ｘ２１はＨまたはＳである；
（ｄ）以下のうちの１つ以上を含む重鎖ＣＤＲ２：
（i）配列番号２８〜３８のＨ１〜Ｈ１１のＣＤＲ２配列と、５つ以下のアミノ酸付加、置換、および／または欠失により異なる重鎖ＣＤＲ２配列；
（ii）ＷＩＮＰＸ７ＳＧＧＴＮＳＡＱＫＦＱＧ（配列番号１７９）；
（iii）ＶＩＸ８Ｘ９ＤＧＸ１０Ｘ１１Ｘ１２ＹＹＡＤＳＶＫＧ（配列番号１８０）；
（iv）Ｘ１３ＩＳＧＸ１４ＧＸ１５Ｘ１６ＴＹＹＡＤＳＶＫＧ（配列番号１８１）；
（v）ＶＩＸ１７ＹＤＧＲＮＫＹＸ１８ＡＤＳＶＫＧ（配列番号１８２）；
ここで、
Ｘ７はＮまたはＹであり；
Ｘ８はＷまたはＧであり；
Ｘ９はＦまたはＹであり；
Ｘ１０はＲまたはＳであり；
Ｘ１１はＮまたはＹであり；
Ｘ１２はＱまたはＫであり；
Ｘ１３はＡまたはＤであり；
Ｘ１４はＳまたはＲであり；
Ｘ１５はＶまたはＧであり；
Ｘ１６はＳまたはＹであり；
Ｘ１７はＷまたはＳであり；および
Ｘ１８はＹまたはＨである；
（ｅ）（ａ）の軽鎖ＣＤＲ１および（ｂ）の軽鎖ＣＤＲ２；
（ｆ）（ａ）の軽鎖ＣＤＲ１および（ｃ）の重鎖ＣＤＲ１；
（ｇ）（ａ）の軽鎖ＣＤＲ１および（ｄ）の重鎖ＣＤＲ２；
（ｈ）（ｂ）の軽鎖ＣＤＲ１および（ｃ）の重鎖ＣＤＲ１；
（ｉ）（ｃ）の重鎖ＣＤＲ１および（ｄ）の重鎖ＣＤＲ２；
（ｊ）（ｂ）の軽鎖ＣＤＲ２および（ｄ）の重鎖ＣＤＲ２；
（ｋ）（ａ）の軽鎖ＣＤＲ１、（ｂ）の軽鎖ＣＤＲ２、および（ｃ）の重鎖ＣＤＲ１；
（ｌ）（ｂ）の軽鎖ＣＤＲ２、（ｃ）の重鎖ＣＤＲ１、および（ｄ）の重鎖ＣＤＲ２；
（ｍ）（ａ）の軽鎖ＣＤＲ１、（ｃ）の重鎖ＣＤＲ１、および（ｄ）の重鎖ＣＤＲ２；
並びに
（ｎ）（ａ）の軽鎖ＣＤＲ１、（ｂ）の軽鎖ＣＤＲ２、（ｃ）の重鎖ＣＤＲ２、および（ｄ）の重鎖ＣＤＲ２；
のうちの１つ以上をさらに含み、
β−Ｋｌｏｔｈｏと特異的に結合する、請求項１に記載の抗原結合タンパク質。 The antigen binding protein
(A) Light chain CDRs comprising one or more of the following:
(I) a light chain CDR1 sequence that differs depending on the CDR1 sequence of L1 to L11 of SEQ ID NOs: 17 to 27 and no more than two amino acid additions, substitutions, deletions, and combinations thereof;
(Ii) RSSQSLVX 22 YX 23 DGNTYLS (SEQ ID NO: 177);
(Iii) SGSSSNIGNYNYVS (SEQ ID NO: 107);
(Vi) QASQDINNYLN (SEQ ID NO: 108);
(V) RASQSVSGNYLA (SEQ ID NO: 109);
(Vi) GVSSGSVSTRYYPS (SEQ ID NO: 110);
here,
X 22 is H or absent; and X 23 is S or absent;
(B) Light chain CDR2 comprising one or more of the following:
(I) a light chain CDR2 sequence that varies depending on the CDR2 sequence of L1 to L11 of SEQ ID NOs: 17 to 27 and no more than two amino acid additions, substitutions, deletions, and combinations thereof;
(Ii) KISNRFS (SEQ ID NO: 112);
(Iii) DNNX 4 RPX 5 (SEQ ID NO: 176);
(Iv) DTNLET (SEQ ID NO: 114);
(V) GASSRAT (SEQ ID NO: 115);
(Vi) STNTRSS (SEQ ID NO: 116);
here,
X 4 is K, N or R; and X 5 is S or absent; and (c) a heavy chain CDR comprising one or more of the following:
(I) a heavy chain CDR1 sequence that differs depending on the CDR1 sequence of H1 to H11 of SEQ ID NOs: 28 to 38 and no more than three amino acid additions, substitutions, deletions, and combinations thereof;
(Ii) X 19 YX 20 MX 21,
here,
X 19 is A, G, R, S, T, or I;
X 20 is Y, G or A; and X 21 is H or S;
(D) Heavy chain CDR2 comprising one or more of the following:
(I) a heavy chain CDR2 sequence that differs by no more than five amino acid additions, substitutions, and / or deletions from a CDR2 sequence of H1-H11 of SEQ ID NOs: 28-38;
(Ii) WINPX 7 SGGTNSAQKFQG (SEQ ID NO: 179);
(Iii) VIX 8 X 9 DGX 10 X 11 X 12 YYADSVKG (SEQ ID NO: 180);
(Iv) X 13 ISGX 14 GX 15 X 16 TYYADSVKG (SEQ ID NO: 181);
(V) VIX 17 YDGRNKYX 18 ADSVKG (SEQ ID NO: 182);
here,
X 7 is N or Y;
X 8 is W or G;
X 9 is F or Y;
X 10 is R or S;
X 11 is N or Y;
X 12 is Q or K;
X 13 is A or D;
X 14 is S or R;
X 15 is V or G;
X 16 is S or Y;
X 17 is W or S; and X 18 is Y or H;
(E) the light chain CDR1 of (a) and the light chain CDR2 of (b);
(F) the light chain CDR1 of (a) and the heavy chain CDR1 of (c);
(G) the light chain CDR1 of (a) and the heavy chain CDR2 of (d);
(H) the light chain CDR1 of (b) and the heavy chain CDR1 of (c);
(I) the heavy chain CDR1 of (c) and the heavy chain CDR2 of (d);
(J) the light chain CDR2 of (b) and the heavy chain CDR2 of (d);
(K) (a) light chain CDR1, (b) light chain CDR2, and (c) heavy chain CDR1;
(L) the light chain CDR2 of (b), the heavy chain CDR1 of (c), and the heavy chain CDR2 of (d);
(M) (a) light chain CDR1, (c) heavy chain CDR1, and (d) heavy chain CDR2;
And (n) (a) light chain CDR1, (b) light chain CDR2, (c) heavy chain CDR2, and (d) heavy chain CDR2;
Further including one or more of
The antigen-binding protein according to claim 1, which specifically binds to β-Klotho. 抗原結合タンパク質が、
（ａ）以下を含む軽鎖可変領域：
（i）配列番号１０６〜１１１のうちの１つ以上を含む軽鎖ＣＤＲ１；
（ii）配列番号：１１２〜１１９のうちの１つ以上を含む軽鎖ＣＤＲ２；
（iii）配列番号１２０〜１２７のうちの１つ以上を含む軽鎖ＣＤＲ３；および
（ｂ）以下を含む重鎖可変領域：
（i）配列番号８３〜８８のうちの１つ以上を含む重鎖ＣＤＲ１；
（ii）配列番号８９〜９７のうちの１つ以上を含む重鎖ＣＤＲ２；および
（iii）配列番号９８〜１０５のうちの１つ以上を含む重鎖ＣＤＲ３；または
（ｃ）（ａ）の軽鎖可変領域および（ｂ）の重鎖可変領域
のうちの１つ以上を含み、
β−Ｋｌｏｔｈｏと特異的に結合する、請求項１に記載の抗原結合タンパク質。 The antigen binding protein
(A) Light chain variable region comprising:
(I) a light chain CDR1 comprising one or more of SEQ ID NOs: 106-111;
(Ii) a light chain CDR2 comprising one or more of SEQ ID NOs: 112-119;
(Iii) a light chain CDR3 comprising one or more of SEQ ID NOS: 120-127; and (b) a heavy chain variable region comprising:
(I) a heavy chain CDR1 comprising one or more of SEQ ID NOs: 83-88;
(Ii) a heavy chain CDR2 comprising one or more of SEQ ID NOs: 89-97; and (iii) a heavy chain CDR3 comprising one or more of SEQ ID NOs: 98-105; or (c) a light chain of (a) One or more of a chain variable region and a heavy chain variable region of (b),
The antigen-binding protein according to claim 1, which specifically binds to β-Klotho. 抗原結合タンパク質が、
（ａ）以下のうちの１つ以上を含む軽鎖可変領域：
（i）配列番号１７〜２７のＬ１〜Ｌ１１のうちの１つ以上を含む、軽鎖可変領域配列と少なくとも８０％の同一性を有するアミノ酸；
（ii）配列番号１７〜２７のＬ１〜Ｌ１１の軽鎖可変領域配列をコードするポリヌクレオチド配列と少なくとも８０％の同一性を有するポリヌクレオチド配列によりコードされるアミノ酸配列；
（ｂ）以下のうちの１つ以上を含む重鎖可変領域：
（i）配列番号２８〜３８のＨ１〜Ｈ１１の重鎖可変領域配列と少なくとも８０％の同一性を有するアミノ酸配列；
（ii）配列番号２８〜３８のＨ１〜Ｈ１１の重鎖可変領域配列をコードするポリヌクレオチド配列と少なくとも８０％の同一性を有するポリヌクレオチド配列によりコードされるアミノ酸配列；並びに
（ｃ）（ａ）の軽鎖可変領域および（ｂ）の重鎖可変領域
のうちの１つ以上を含み、
β−Ｋｌｏｔｈｏと特異的に結合する、請求項１に記載の抗原結合タンパク質。 The antigen binding protein
(A) a light chain variable region comprising one or more of the following:
(I) an amino acid having at least 80% identity with a light chain variable region sequence comprising one or more of L1-L11 of SEQ ID NOs: 17-27;
(Ii) an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with the light chain variable region sequence of L1-L11 of SEQ ID NOs: 17-27;
(B) a heavy chain variable region comprising one or more of the following:
(I) an amino acid sequence having at least 80% identity with the heavy chain variable region sequence of H1-H11 of SEQ ID NOs: 28-38;
(Ii) an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with the heavy chain variable region sequence of H1-H11 of SEQ ID NOs: 28-38; and (c) (a) One or more of a light chain variable region of (b) and a heavy chain variable region of (b),
The antigen-binding protein according to claim 1, which specifically binds to β-Klotho. 抗原結合タンパク質が、
（ａ）配列番号１７〜２７のＬ１〜Ｌ１１のうちの１つ以上を含む、軽鎖可変領域配列；
（ｂ）配列番号２８〜３８のＨ１〜Ｈ１１のうちの１つ以上を含む、重鎖可変領域配列；並びに
（ｃ）（ａ）の軽鎖可変領域および（ｂ）の重鎖可変領域
のうちの１つ以上を含み、
β−Ｋｌｏｔｈｏと特異的に結合する、請求項１に記載の単離された抗原結合タンパク質。 The antigen binding protein
(A) a light chain variable region sequence comprising one or more of L1-L11 of SEQ ID NOs: 17-27;
(B) a heavy chain variable region sequence comprising one or more of H1-H11 of SEQ ID NOs: 28-38; and (c) a light chain variable region of (a) and a heavy chain variable region of (b) Including one or more of
2. The isolated antigen binding protein of claim 1 that specifically binds to [beta] -Klotho. 軽鎖可変領域および重鎖可変領域が、Ｌ１Ｈ１、Ｌ２Ｈ２、Ｌ３Ｈ３、Ｌ４Ｈ４、Ｌ５Ｈ５、Ｌ６Ｈ６、Ｌ７Ｈ７、Ｌ８Ｈ８、Ｌ９Ｈ９、Ｌ１０Ｈ１０およびＬ１１Ｈ１１から成る組み合わせの群から選択され、
抗原結合タンパク質がβ−Ｋｌｏｔｈｏと特異的に結合する、請求項５に記載の抗原結合タンパク質。 The light chain variable region and the heavy chain variable region are selected from the group of combinations consisting of L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10 and L11H11;
The antigen-binding protein according to claim 5, wherein the antigen-binding protein specifically binds to β-Klotho. 抗原結合タンパク質が、
（ａ）配列番号１３の軽鎖定常配列；
（ｂ）配列番号１５の軽鎖定常配列；
（ｃ）配列番号９の重鎖定常配列；並びに
（ｄ）配列番号１３または配列番号１５の軽鎖定常配列および配列番号９の重鎖定常配列
を含む、請求項６に記載の抗原結合タンパク質。 The antigen binding protein
(A) the light chain constant sequence of SEQ ID NO: 13;
(B) the light chain constant sequence of SEQ ID NO: 15;
The antigen binding protein of claim 6, comprising (c) a heavy chain constant sequence of SEQ ID NO: 9; and (d) a light chain constant sequence of SEQ ID NO: 13 or SEQ ID NO: 15 and a heavy chain constant sequence of SEQ ID NO: 9. 抗原結合タンパク質が、ヒト抗体、ヒト化抗体、キメラ抗体、モノクローナル抗体、ポリクローナル抗体、組換え抗体、抗原結合抗体断片、単鎖抗体、二重特異性抗体、三重特異性抗体（triabody）、四重特異性抗体（tetrabody）、Ｆａｂ断片、Ｆ（ｆａ’）ｘ断片、ドメイン抗体、ＩｇＤ抗体、ＩｇＥ抗体、ＩｇＭ抗体、ＩｇＧ１抗体、ＩｇＧ２抗体、ＩｇＧ３抗体、ＩｇＧ４抗体、またはヒンジ領域に少なくとも１つの変異を有するＩｇＧ４抗体を含む、請求項１に記載の抗原結合タンパク質。   Antigen binding protein is human antibody, humanized antibody, chimeric antibody, monoclonal antibody, polyclonal antibody, recombinant antibody, antigen binding antibody fragment, single chain antibody, bispecific antibody, trispecific antibody (triabody), quadruple Specific antibody (tetrabody), Fab fragment, F (fa ′) x fragment, domain antibody, IgD antibody, IgE antibody, IgM antibody, IgG1 antibody, IgG2 antibody, IgG3 antibody, IgG4 antibody, or at least one mutation in the hinge region 2. The antigen binding protein of claim 1 comprising an IgG4 antibody having β−Ｋｌｏｔｈｏと結合する際、
（ａ）参照抗体と実質的に同じＫｄでβ−Ｋｌｏｔｈｏと結合し；
（ｂ）ＥＬＫ−ルシフェラーゼレポーターアッセイで測定して、配列番号２の成熟型を含む野生型ＦＧＦ２１標準物質により誘発されるシグナル伝達の１０％以上のＦＧＦ２１様シグナル伝達を誘発し；
（ｃ）以下から成る群から選択されるアッセイにおいて、１０ｎＭ以下のＥＣ５０のＦＧＦ２１様シグナル伝達を示し：
（i）ＦＧＦＲ１ｃ／β−Ｋｌｏｔｈｏを介する、ｉｎ ｖｉｔｒｏ組換え細胞ベースのアッセイ；
（ｄ）ｉｎ ｖｉｔｒｏ組換え型ＦＧＦＲ１ｃ受容体媒介レポーターアッセイにおいて、β−Ｋｌｏｔｈｏが存在する場合、ＦＧＦＲ１ｃ上で、１０ｎＭ未満のＥＣ５０のアゴニスト活性を示し；および
（ｅ）ｉｎ ｖｉｔｒｏ組換え型ＦＧＦＲ１ｃ受容体媒介レポーターアッセイにおいて、β−Ｋｌｏｔｈｏが存在しない場合、ＦＧＦＲ１ｃ上で、１μＭ超のＥＣ５０のアゴニスト活性を示し；並びに
（ｆ）β−Ｋｌｏｔｈｏとの結合に対して参照抗体と競合し、
前記参照抗体が、軽鎖および重鎖可変領域配列の以下の組み合わせ：Ｌ１Ｈ１、Ｌ２Ｈ２、Ｌ３Ｈ３、Ｌ４Ｈ４、Ｌ５Ｈ５、Ｌ６Ｈ６、Ｌ７Ｈ７、Ｌ８Ｈ８、Ｌ９Ｈ９、Ｌ１０Ｈ１０およびＬ１１Ｈ１１のうちの１つ以上を含む、請求項１に記載の抗原結合タンパク質。 When binding to β-Klotho,
(A) binds to β-Klotho with substantially the same Kd as the reference antibody;
(B) elicit FGF21-like signaling that is 10% or more of that induced by wild-type FGF21 standards, including the mature form of SEQ ID NO: 2, as measured by ELK-luciferase reporter assay;
(C) Show FGF21-like signaling with an EC50 of 10 nM or less in an assay selected from the group consisting of:
(I) an in vitro recombinant cell-based assay via FGFR1c / β-Klotho;
(D) in an in vitro recombinant FGFR1c receptor-mediated reporter assay, when β-Klotho is present, exhibits an agonist activity of EC50 of less than 10 nM on FGFR1c; and (e) an in vitro recombinant FGFR1c receptor In a mediated reporter assay, in the absence of β-Klotho, exhibits an agonist activity of EC50 of greater than 1 μM on FGFR1c; and (f) competes with a reference antibody for binding to β-Klotho;
The reference antibody comprises one or more of the following combinations of light and heavy chain variable region sequences: L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10 and L11H11. 1. The antigen binding protein according to 1. β−Ｋｌｏｔｈｏと結合する際、
（ａ）動物モデルにおいて血糖を低下させ；
（ｂ）動物モデルにおいて血清脂質値を低下させ；または
（ｃ）（ａ）かつ（ｂ）である、
請求項９に記載の抗原結合タンパク質。 When binding to β-Klotho,
(A) reducing blood glucose in animal models;
(B) reduce serum lipid levels in an animal model; or (c) (a) and (b)
The antigen-binding protein according to claim 9. 請求項１または９に記載の抗原結合タンパク質を、その薬剤的に許容できる担体との混合物中に含む、医薬組成物。   A pharmaceutical composition comprising the antigen binding protein of claim 1 or 9 in a mixture with its pharmaceutically acceptable carrier. 請求項４に記載の抗原結合タンパク質の軽鎖可変領域、重鎖可変領域、または両方をコードするポリヌクレオチド配列を含む、単離された核酸。   5. An isolated nucleic acid comprising a polynucleotide sequence encoding the light chain variable region, heavy chain variable region, or both of the antigen binding protein of claim 4. 配列が、配列番号１７〜２７のＬ１〜Ｌ１１、配列番号２８〜３８のＨ１〜Ｈ１１、または両方から選ばれる、請求項１２に記載の単離された核酸。   13. The isolated nucleic acid of claim 12, wherein the sequence is selected from L1-L11 of SEQ ID NOs: 17-27, H1-H11 of SEQ ID NOs: 28-38, or both. 請求項１３に記載の核酸を含む、発現ベクター。   An expression vector comprising the nucleic acid according to claim 13. 請求項１３に記載の核酸を含む、単離された細胞。   An isolated cell comprising the nucleic acid of claim 13. 核酸を含む発現ベクターを含む、請求項１５に記載の単離された細胞。   The isolated cell of claim 15, comprising an expression vector comprising a nucleic acid. β−Ｋｌｏｔｈｏと特異的に結合する抗原結合タンパク質の製造方法であって、請求項１６に記載の宿主細胞を、前記宿主細胞が前記抗原結合タンパク質を発現することを可能にする条件下でインキュベートすることを含む、方法。   17. A method of producing an antigen binding protein that specifically binds to [beta] -Klotho, wherein the host cell of claim 16 is incubated under conditions that allow the host cell to express the antigen binding protein. Including the method. 以下：ＴＲＬＷＫＹＷＶ（配列番号１８４）；ＲＲＬＹＩＦＷＥ（配列番号１８５）；ＹＫＡＷＧＹＹＶ（配列番号１８６）；ＹＱＡＷＧＹＹＶ（配列番号１８７）；ＹＱＡＷＧＹＬＶ（配列番号１８８）；ＹＱＡＷＧＹＦＶ（配列番号１８９）；ＦＴＷＶＦＷＮＶ（配列番号１９０）；ＹＱＶＷＧＹＦＶ（配列番号１９１）；ＹＫＷＬＫＷＮＬ（配列番号１９２）；ＲＲＬＹＩＦＥＷ（配列番号１９３）；ＷＡＥＲＧＧ（配列番号１９４）；ＧＧＷＡＶＧＲＩ（配列番号１９５）；ＹＫＹＬＶＦＷＶ（配列番号１９６）；ＹＫＹＬＳＹＷＶ（配列番号１９７）；ＹＫＴＡＷＹＷＫ（配列番号１９８）；ＹＶＦＨＫＷＷＶ（配列番号１９９）；ＹＶＦＹＬＷＷＫ（配列番号２００）；ＹＲＷＬＨＷＨＶ（配列番号２０１）；ＹＫＦＬＦＷＨＡ（配列番号２０２）；ＲＲＱＷＧＦＷＶ（配列番号２０３）；ＹＳＡＷＳＦＷＶ（配列番号２０４）；ＬＡＲＷＧＦＷＶ（配列番号２０５）；ＹＤＡＷＧＹＷＶ（配列番号２０６）；ＷＲＫＹＹＨＦＷＶＳ（配列番号２０７）；ＫＲＬＹＧＬＦＷＹＤ（配列番号２０８）；ＫＫＨＷＳＳＬＦＦＥ（配列番号２０９）；ＫＡＷＰＹＳＷＥＡＶ（配列番号２１０）；ＥＷＹＣＧＶＬＦＮＣＱＱ（配列番号２１１）；ＨＦＧＣＧＶＩＦＮＣＶＳＤ（配列番号２１２）；ＷＥＬＣＡＳＧＹＧＷＣＹＬＨ（配列番号２１３）；ＡＰＳＣＫＳＹＩＧＦＧＬＹＨＣＷＤＧ（配列番号２１４）；およびＨＦＫＣＧＭＧＬＦＥＣＡＤＰ（配列番号２１５）
のうちの１つ以上を含む、ポリペプチド。 Following: TRLWKYWV (SEQ ID NO: 184); RRLYIFWE (SEQ ID NO: 185); YKAWGYYV (SEQ ID NO: 186); YQAWGYYV (SEQ ID NO: 187); YQAWGYLV (SEQ ID NO: 188); YQAWGYFV (SEQ ID NO: 189); YQVWGYFV (SEQ ID NO: 191); YKWLKWNL (SEQ ID NO: 192); RRLYIFEW (SEQ ID NO: 193); WAERGG (SEQ ID NO: 194); GWWAVGRI (SEQ ID NO: 195); YKYLVFWV (SEQ ID NO: 196); YKTAWYWK (SEQ ID NO: 198); YVFHKWWV (SEQ ID NO: 199); YVFYLWWK (SEQ ID NO: 200); YRWWLHWHHV (SEQ ID NO: 201); YKFLFWHA SEQ ID NO: 202); RRQWGFWV (SEQ ID NO: 203); YSAWSFWV (SEQ ID NO: 204); LARWGFWV (SEQ ID NO: 205); YDAWGYWV (SEQ ID NO: 206); WRKYYHFWVS (SEQ ID NO: 207); KRLYGLFWYD (SEQ ID NO: 208); KAWPYSWEAV (SEQ ID NO: 210); EWYCGVLFNCQQ (SEQ ID NO: 211); HFGCGVIFNCVSD (SEQ ID NO: 212); WELCSGYGWCYLH (SEQ ID NO: 213);
A polypeptide comprising one or more of the following. 重鎖が、ＦＧＦＲ１ｃ、ＦＧＦＲ２ｃ、ＦＧＦＲ３ｃ、およびＦＧＦＲ４のうちの１つ以上に特異的に結合するペプチドをさらに含む、請求項１〜１０のいずれかに記載の抗原結合タンパク質。   The antigen-binding protein according to any of claims 1 to 10, wherein the heavy chain further comprises a peptide that specifically binds to one or more of FGFR1c, FGFR2c, FGFR3c, and FGFR4. ペプチドが、以下：ＴＲＬＷＫＹＷＶ（配列番号１８４）；ＲＲＬＹＩＦＷＥ（配列番号１８５）；ＹＫＡＷＧＹＹＶ（配列番号１８６）；ＹＱＡＷＧＹＹＶ（配列番号１８７）；ＹＱＡＷＧＹＬＶ（配列番号１８８）；ＹＱＡＷＧＹＦＶ（配列番号１８９）；ＦＴＷＶＦＷＮＶ（配列番号１９０）；ＹＱＶＷＧＹＦＶ（配列番号１９１）；ＹＫＷＬＫＷＮＬ（配列番号１９２）；ＲＲＬＹＩＦＥＷ（配列番号１９３）；ＷＡＥＲＧＧ（配列番号１９４）；ＧＧＷＡＶＧＲＩ（配列番号１９５）；ＹＫＹＬＶＦＷＶ（配列番号１９６）；ＹＫＹＬＳＹＷＶ（配列番号１９７）；ＹＫＴＡＷＹＷＫ（配列番号１９８）；ＹＶＦＨＫＷＷＶ（配列番号１９９）；ＹＶＦＹＬＷＷＫ（配列番号２００）；ＹＲＷＬＨＷＨＶ（配列番号２０１）；ＹＫＦＬＦＷＨＡ（配列番号２０２）；ＲＲＱＷＧＦＷＶ（配列番号２０３）；ＹＳＡＷＳＦＷＶ（配列番号２０４）；ＬＡＲＷＧＦＷＶ（配列番号２０５）；ＹＤＡＷＧＹＷＶ（配列番号２０６）；ＷＲＫＹＹＨＦＷＶＳ（配列番号２０７）；ＫＲＬＹＧＬＦＷＹＤ（配列番号２０８）；ＫＫＨＷＳＳＬＦＦＥ（配列番号２０９）；ＫＡＷＰＹＳＷＥＡＶ（配列番号２１０）；ＥＷＹＣＧＶＬＦＮＣＱＱ（配列番号２１１）；ＨＦＧＣＧＶＩＦＮＣＶＳＤ（配列番号２１２）；ＷＥＬＣＡＳＧＹＧＷＣＹＬＨ（配列番号２１３）；ＡＰＳＣＫＳＹＩＧＦＧＬＹＨＣＷＤＧ（配列番号２１４）；およびＨＦＫＣＧＭＧＬＦＥＣＡＤＰ（配列番号２１５）
のうちの１つ以上を含む、請求項１９に記載の抗原結合タンパク質重鎖。 The peptides are: TRLWKYWV (SEQ ID NO: 184); RRLYIFWE (SEQ ID NO: 185); YKAWGYYV (SEQ ID NO: 186); YQAWGYYV (SEQ ID NO: 187); YQAWGYLV (SEQ ID NO: 188); YQAWGYFV (SEQ ID NO: 189F) YQVWGYFV (SEQ ID NO: 191); YKWLKWNL (SEQ ID NO: 192); RRLYIFEW (SEQ ID NO: 193); WAERGG (SEQ ID NO: 194); GWWAVGRI (SEQ ID NO: 195); YKYLVFWV (SEQ ID NO: 196); 197); YKTAWYWK (SEQ ID NO: 198); YVFHKWWV (SEQ ID NO: 199); YVFYLWWK (SEQ ID NO: 200); YRWWLHWHV (SEQ ID NO: 201); YK RFWHA (SEQ ID NO: 202); RRQWGFWV (SEQ ID NO: 203); YSAWSFWV (SEQ ID NO: 204); LARWGFWV (SEQ ID NO: 205); YDAWGYWV (SEQ ID NO: 206); WRKYYHFFWVS (SEQ ID NO: 207); KRLYGLFWYD (SEQ ID NO: 208); KAWPYSWEAV (SEQ ID NO: 210); EWYCGVLFNCQQ (SEQ ID NO: 211); HFGCGVIFNCVSD (SEQ ID NO: 212); WELCASGYGWCYLH (SEQ ID NO: 213);
20. The antigen binding protein heavy chain of claim 19, comprising one or more of: 重鎖がＣＨ２ループ、ＣＨ３ループ、またはＣＨ２およびＣＨ３ループの両方を含む、請求項２０に記載の抗原結合タンパク質重鎖。   21. The antigen binding protein heavy chain of claim 20, wherein the heavy chain comprises a CH2 loop, a CH3 loop, or both CH2 and CH3 loops. 重鎖がＣＨ３ループを含む、請求項２１に記載の重鎖。   The heavy chain of claim 21, wherein the heavy chain comprises a CH3 loop. ＣＨ３ループがペプチドを含む、請求項２２に記載の重鎖。   23. The heavy chain of claim 22, wherein the CH3 loop comprises a peptide. 重鎖がＣＨ２ループを含む、請求項２１に記載の重鎖。   The heavy chain of claim 21, wherein the heavy chain comprises a CH2 loop. ＣＨ２ループがペプチドを含む、請求項２４に記載の重鎖。   25. The heavy chain of claim 24, wherein the CH2 loop comprises a peptide. 請求項２３または２５に記載の重鎖を含む、抗原結合タンパク質。   An antigen-binding protein comprising the heavy chain according to claim 23 or 25. 請求項１９に記載の抗原結合タンパク質を、その薬剤的に許容できる担体との混合物中に含む、医薬組成物。   20. A pharmaceutical composition comprising the antigen binding protein of claim 19 in a mixture with its pharmaceutically acceptable carrier. 請求項１９に記載の抗原結合タンパク質の、軽鎖可変領域、重鎖可変領域、あるいは両方をコードするポリヌクレオチド配列を含む、単離された核酸。   21. An isolated nucleic acid comprising a polynucleotide sequence encoding a light chain variable region, a heavy chain variable region, or both of the antigen binding protein of claim 19. 配列が、配列番号１７〜２７のＬ１〜Ｌ１１、配列番号２８〜３８のＨ１〜Ｈ１１、あるいは両方から選ばれる、請求項２８に記載の単離された核酸。   30. The isolated nucleic acid of claim 28, wherein the sequence is selected from L1-L11 of SEQ ID NOs: 17-27, H1-H11 of SEQ ID NOs: 28-38, or both. 請求項２９に記載の核酸を含む、発現ベクター。   An expression vector comprising the nucleic acid according to claim 29. 請求項２９に記載の核酸を含む、単離された細胞。   30. An isolated cell comprising the nucleic acid of claim 29. 核酸を含む発現ベクターを含む、請求項３１に記載の単離された細胞。   32. The isolated cell of claim 31, comprising an expression vector comprising a nucleic acid. β−Ｋｌｏｔｈｏと特異的に結合する抗原結合タンパク質の製造方法であって、請求項３２に記載の宿主細胞を、前記宿主細胞が前記抗原結合タンパク質を発現することを可能にする条件下でインキュベートすることを含む、方法。   33. A method of producing an antigen binding protein that specifically binds to [beta] -Klotho, wherein the host cell of claim 32 is incubated under conditions that allow the host cell to express the antigen binding protein. Including the method. （ａ）抗原結合成分；および
（ｂ）ＦＧＦ２１成分；
を含む、抗原結合タンパク質−ＦＧＦ２１融合体。 (A) an antigen-binding component; and (b) an FGF21 component;
An antigen binding protein-FGF21 fusion. 抗原結合成分が、請求項１に記載の抗原結合タンパク質を含む、請求項３４に記載の抗原結合タンパク質−ＦＧＦ２１融合体。   35. The antigen binding protein-FGF21 fusion of claim 34, wherein the antigen binding component comprises the antigen binding protein of claim 1. ＦＧＦ２１成分が、配列番号３４１の少なくとも２５個の連続した残基を含む、請求項３４に記載の抗原結合タンパク質−ＦＧＦ２１融合体。   35. The antigen binding protein-FGF21 fusion of claim 34, wherein the FGF21 component comprises at least 25 consecutive residues of SEQ ID NO: 341. ＦＧＦ２１成分が、（ａ）配列番号３４２または（ｂ）配列番号３４３のうちの１つを含む、請求項３６に記載の抗原結合タンパク質−ＦＧＦ２１融合体。   37. The antigen binding protein-FGF21 fusion of claim 36, wherein the FGF21 component comprises one of (a) SEQ ID NO: 342 or (b) SEQ ID NO: 343. リンカーをさらに含む、請求項３４に記載の抗原結合タンパク質−ＦＧＦ２１融合体。   35. The antigen binding protein-FGF21 fusion of claim 34, further comprising a linker. （ａ）抗原結合成分が、配列番号１８および配列番号２９を含み；並びに
（ｂ）ＦＧＦ２１成分が、
（i）配列番号３４２；および
（ii）配列番号３４３
のうちの１つを含む、請求項３４に記載の抗原結合タンパク質−ＦＧＦ２１融合体。 (A) the antigen binding component comprises SEQ ID NO: 18 and SEQ ID NO: 29; and (b) the FGF21 component is
(I) SEQ ID NO: 342; and (ii) SEQ ID NO: 343
35. The antigen binding protein-FGF21 fusion of claim 34, comprising one of 抗原結合成分が、（Ｇ４Ｓ）３、（配列番号３３６）（Ｇ４Ｓ）６（配列番号３３７）、（Ｇ４Ｓ）９（配列番号３３８）、（Ｇ４Ｓ）１２（配列番号３３９）および（Ｇ４Ｓ）１５（配列番号３４０）から成る群から選択されるリンカーによって、ＦＧＦ２１成分に連結されている、請求項３９に記載の抗原結合タンパク質−ＦＧＦ２１融合体。 The antigen-binding component is (G 4 S) 3 , (SEQ ID NO: 336) (G 4 S) 6 (SEQ ID NO: 337), (G 4 S) 9 (SEQ ID NO: 338), (G 4 S) 12 (SEQ ID NO: 339) and (G 4 S) 15 (by linker selected from the group consisting of SEQ ID NO: 340), is connected to the FGF21 component, antigen binding protein -FGF21 fusion of claim 39. ＦＧＦ２１成分が、抗原結合成分の重鎖に連結されている、請求項３９に記載の抗原結合タンパク質−ＦＧＦ２１融合体。   40. The antigen binding protein-FGF21 fusion of claim 39, wherein the FGF21 component is linked to the heavy chain of the antigen binding component. 重鎖が、配列番号３１６、３２０、３２２、３２４、３２６、３１８、３２８、３３０、３３２および３３４のうちの１つ以上を含む、請求項４１に記載の抗原結合タンパク質−ＦＧＦ２１融合体。   42. The antigen binding protein-FGF21 fusion of claim 41, wherein the heavy chain comprises one or more of SEQ ID NOs: 316, 320, 322, 324, 326, 318, 328, 330, 332 and 334. ＦＧＦ２１成分が、抗原結合成分の軽鎖に連結されている、請求項３９に記載の抗原結合タンパク質−ＦＧＦ２１融合体。   40. The antigen binding protein-FGF21 fusion of claim 39, wherein the FGF21 component is linked to the light chain of the antigen binding component. β−Ｋｌｏｔｈｏ、またはβ−ＫｌｏｔｈｏならびにＦＧＦＲ１ｃ、ＦＧＦＲ２ｃ、ＦＧＦＲ３ｃ、およびＦＧＦＲ４のうちの１つ以上に結合した際、
（ａ）動物モデルにおいて血糖を低下させ；
（ｂ）動物モデルにおいて血清脂質値を低下させ；および
（ｃ）（ａ）かつ（ｂ）である、
請求項３４に記載の抗原結合タンパク質。 When bound to β-Klotho, or β-Klotho and one or more of FGFR1c, FGFR2c, FGFR3c, and FGFR4,
(A) reducing blood glucose in animal models;
(B) reducing serum lipid levels in an animal model; and (c) (a) and (b).
35. An antigen binding protein according to claim 34. 請求項３４に記載の抗原結合成分の軽鎖、重鎖あるいは両方をコードする単離された核酸であって、
（ａ） 配列番号１７〜２７のＬ１−Ｌ１１；
（ｂ） 配列番号２８〜３８のＨ１−Ｈ１１；または
（ｃ） 配列番号３１６、３２０、３２２、３２４、３２６、３１８、３２８、３３０、３３２または３３４
を含む、核酸。 An isolated nucleic acid encoding the light chain, heavy chain, or both of the antigen binding component of claim 34, comprising:
(A) L1-L11 of SEQ ID NOs: 17-27;
(B) H1-H11 of SEQ ID NOs: 28-38; or (c) SEQ ID NOs: 316, 320, 322, 324, 326, 318, 328, 330, 332 or 334
A nucleic acid comprising 請求項４５に記載の核酸を含む、発現ベクター。   An expression vector comprising the nucleic acid according to claim 45. 請求項４６に記載の核酸を含む、単離された細胞。   49. An isolated cell comprising the nucleic acid of claim 46. 核酸を含む発現ベクターを含む、請求項４７に記載の単離された細胞。   48. The isolated cell of claim 47, comprising an expression vector comprising a nucleic acid. 請求項３４に記載の抗原結合タンパク質−ＦＧＦ２１融合体を含み、薬剤的に許容できる担体をさらに含む、医薬組成物。   35. A pharmaceutical composition comprising the antigen binding protein-FGF21 fusion of claim 34 and further comprising a pharmaceutically acceptable carrier. 対象において、血糖を低下させることにより治療可能である状態を予防または治療するための、請求項４９に記載の医薬組成物。   50. The pharmaceutical composition according to claim 49 for preventing or treating a condition in a subject that is treatable by lowering blood glucose. 前記状態が２型糖尿病、肥満症、脂質異常症、非アルコール性脂肪性肝炎、心血管疾患、およびメタボリックシンドロームから選ばれる、請求項４９に記載の医薬組成物。   50. The pharmaceutical composition according to claim 49, wherein the condition is selected from type 2 diabetes, obesity, dyslipidemia, non-alcoholic steatohepatitis, cardiovascular disease, and metabolic syndrome.
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